In this R21 program, we propose to develop a highly-integrated and highly-sensitive nanowire probe platform for single cell endoscopy. At the center of this platform lies the integrated flexible nanowire on the tip of a near- field scanning optical microscopy (NSOM) probe. This program will be built upon our extensive expertise in nanostructure synthesis/assembly, systems integration and nanowire based photonics. Our extensive capabilities and expertise will put us in a unique position to achieve potential breakthroughs and open up new possibilities in single cell imaging and probing. Developing of such flexible nanowire probes would enable us to monitor in-vivo biological processes within single living cells and will greatly improve our fundamental understanding of cell functions, intracellular physiological processes, cellular signal pathway, and thereby revolutionalizes cell biology. We will successfully develop a prototype for NSOM-nanowire probe and demonstrate its proof-of-principle applications for intracellular imaging and probing. We will develop and optimize strategies to assemble these cell endoscopy nanowire probes, i.e., direct nanomanipulation and attachment of nanowires onto NSOM probes. We will test two types of nanowires as sub-wavelength optical waveguides for this study. One is conventional dielectric materials such as SnO2, the other one being materials with strong non-linear optical properties, such as KNbO3. There are several key features associated with these proposed cell endoscopy probes: 1. Minimal invasiveness. The nanowires used will generally have diameters of sub-100 nm and with high aspect ratio. This structural feature ensures the non-invasiveness of the proposed platforms. 2. High flexibility. These nanowires are highly flexible and yet mechanically robust. The twisting and bending in these nanowires will not cause significant optical propagation loss, and greatly ease the application of such probes in single cell imaging. 3. High refractive index. As a result, these nanowires are efficient sub-wavelength optical waveguides even in high-index physiological liquids and/or living cell environments. 4. Evanescent wave optical sensing principle with highly localized excitation and detection scheme. Because of the subwavelength optical waveguiding nature of these nanowires, the probe volume of these nanowires can be limited to the very tip of the nanowires (i.e. down to pico- and femtoliter). 5. Nonlinear optical conversion capability. This application of the nonlinear optical nanowires into the proposed probe platforms will introduce two important features: subwavelength waveguiding and frequency conversion capability. We will be able to input IR beam at one end of the nanowires and use the visible or UV output on the other end to do the cell imaging/probing. The use of IR as input beam would again greatly benefit the entire imaging process in realistic physiological environments. Such novel nanowire probes promise intracellular imaging with greatly enhanced 3-dimensional spatial resolution as well as temporal resolution. In addition, these nanowire probes could also be used to spot- delivery or extraction of chemicals (proteins/DNAs) from single living cells with much improved spatial resolution as compared to conventional delivery/extraction methods.